ABSTRACT
In sporadic Alzheimer's disease (AD), an imbalance between production and clearance of amyloid-ß (Aß) peptides seems to account for enhanced Aß accumulation. The metalloprotease neprilysin (NEP) is an important Aß degrading enzyme as shown by a variety of in vitro and in vivo studies. While the degradation of full-length Aß peptides such as Aß1-40 and Aß1-42 is well established, it is less clear whether NEP is also capable of degrading N-terminally truncated Aß species such as the common variant Aß4-42. In the present report, we confirmed the degradation of Aß4-x species by neprilysin using in vitro digestion and subsequent analysis using gel-based assays and mass spectrometry. By crossing Tg4-42 mice expressing only Aß4-42 peptides with homozygous NEP-knock-out mice (NEP-/-), we were able to demonstrate that NEP deficiency increased hippocampal intraneuronal Aß levels and aggravated neuron loss in the Tg4-42 transgenic mouse model of AD.
